Conventional benzodiazepine anxiolytics are often associated with adverse effects such as motor impairment, excessive sedation, tolerance for the therapeutic effect, physical dependence, abuse liability, cognitive impairments, or toxic effects in overdose. The benzodiazepine of the present invention is useful for treating acute and chronic anxiety disorders (including but not limited to generalized anxiety disorder, panic disorder, social and other phobias, post-traumatic stress disorder, acute anxiety crises) and is not only rapid acting and efficacious in mild-to-severe anxiety disorders and effective when given daily (as once daily, b.i.d. or t.i.d) but shows either no, or substantially less, of the above mentioned adverse side effects.
The present invention relates to 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepin-6-one (I) 
and pharmaceutically acceptable acid addition salts thereof.
This compound and its salts are novel and have valuable pharmacodynamic properties. They are therefore suitable for therapeutic purposes, especially for anxiolytic and/or anticonvulsant purposes and/or for the non-sedative treatment of insomnia across a dose range in which no appreciable sedation and/or motoric impairment occurs.
Objects of the present invention are the above mentioned compound and salts thereof per se and as therapeutically active substances, their manufacture and their use for therapeutic purposes or for the production of corresponding medicaments, as well as medicaments containing the above compound or a salt thereof and the production of such medicaments.
The compound of the invention and its pharmaceutically acceptable acid addition salts can be manufactured, for instance, according to the synthesis path depicted in Reaction Scheme 1 
The benzodiazepine according to the present invention exhibits high affinity in vitro binding to benzodiazepine receptors, as well as rapid onset and robust therapeutic effects in such indications as anxiety disorders, insomnia, mood disorders, psychotic symptoms and disorders, and convulsive disorders (see: Hollister, L. E. et al., Clinical uses of benzodiazepines. J. Clin. Psychopharmacol. 13 (Suppl. 1): 1S-169S, 1993).
In particular, the benzodiazepine of the present invention is useful for treating acute and chronic anxiety disorders (including but not limited to generalized anxiety disorder, panic disorder, social and other phobias, post-traumatic stress disorder, acute anxiety crises) and is not only rapid acting and efficacious in mild-to-severe anxiety disorders and effective when given daily (as once daily, b.i.d. or t.i.d) but shows either no, or substantially less, adverse effects of the sorts characteristic of the known conventional benzodiazepine anxiolytics, such as motor impairment, excessive sedation, tolerance for the therapeutic effect, physical dependence (and the resultant withdrawal symptoms), abuse liability (i.e., psychological dependence), cognitive impairments, drug interactions due to different causes (especially interaction with ethanol or with substances commonly used within that patient population), or toxic effects in overdose (due either to exaggerated pharmacological effects or to non-specific effects of the compound itself at high doses). The pharmacological profile of the compound according to the present invention involves a clear separation between the therapeutic dose range and the doses producing adverse effects based on the results obtained in animals.
The preclinical pharmacological profile of the compound of the present invention for treatment of anxiety disorders, and/or treatment of convulsions and/or non-sedative treatment of sleep disorders involves no, or only minimal motor impairment, in a standard test of motor performance in animals (e.g. rotarod test in mice with motor function evaluated in the same animals at different time points up to 1 hour after intravenous injection). It has been shown for the compound of the present invention that the ED50 (or doses producing impairment in 50% of the animals) for a rotarod deficit is greater than about 10 mg/kg i.v., and this is consistently observed at different time points across the entire period of measurement. Moreover, the pharmacological profile of the compound of the present invention involves a very high affinity in vitro binding to the benzodiazepine receptor (3H-flumazenil in vitro binding assay using homogenized rat cortex) with a pKi value of 9.1 together with a potent anxiolytic-like effect in a mouse model of anxiety.
The compound of the present invention has shown, in the pre-clinical stage, further advantages which overcome several problems typical of the known conventional products. For example, not only is it active in a mouse model of anxiety but additionally it has shown low ethanol interaction in mice, minimal withdrawal signs in chronically treated mice subsequently challenged with a benzodiazepine receptor antagonist (e.g., sarmazenil), minimal reduction (so-called tolerance) of the anxiolytic effect in mice after chronic treatment, or minimal cognitive impairment in rats. In addition, low doses of the benzodiazepine of the present invention are active in an animal model of anxiety and show anticonvulsant effects in animals (for paradigm examples see: Martin and Haefely, Drugs used for the treatment of anxiety and sleep disorders. In: Principles of Pharmacology: Basic Concepts and Clinical Applications, edited by P. Munson et al., New York: Chapman and Hall, 1995, pp. 243-277). Moreover, the benzodiazepine according to the present invention produces minimal or no inhibition of cytochrome P450 isoenzymes, thus reducing the risk of drug-drug interactions due to metabolic cause.
The affinity of the compound of the invention to the central benzodiazepine receptors was established in vitro according to the methods described in Nature 294, 763-765 (1981) and J. Neurochemistry 37, 714-722 (1981). According to these methods, the inhibition of the binding of tritiated flumazenil to the specific benzodiazepine receptors in the cortex of rats by the respective test substance is determined. The affinity was calculated as pKi (for background information on pKi see: Cheng, Y. and W. H. Prusoff, Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (IC50) of an enzymatic reaction. Biochem. Pharmac. 22: 3099-3108, 1973) as the measure of the specific binding of tritiated flumazenil to specific benzodiazepine receptors in the cortex of rat.
The motor impairing properties of the compound of the invention can be determined, for example, in the rotating rod test (rotarod test). Mice (Ibm: MORO (SPF); RCC Ltd., 4414 Fxc3xcllinsdorf, Switzerland) weighing about 20-30 g are used for this test. These mice were housed in Macrolon(copyright) type I cages for one or more days following arrival in the laboratory colony (12:12 hour light-dark cycle). They have free access to a standard rodent diet (Kliba Mxc3xchlen, Kaiseraugst, Switzerland) and tap water in the home cage up to testing. They are brought into the test laboratory at least 30 min before the test which was done during the light portion of the day-night cycle. In the rotating rod test the animals are placed on a horizontally arranged, smooth metal rod having a diameter of 3 cm, which is rotated at 2 revolutions per min. Initially, the animals are given the opportunity of familiarizing themselves with the test situation for at least 30 sec. Subsequently, those animals which succeed in remaining on the rod for at least 1 min are selected for use in the test. These selected animals are then given the test preparations intravenously in different dosages. At various points in time post-injection, it is then determined whether the animals are able to remain wallking on the rod for a minimum period (minimum period of 10 sec at time points 15 sec. 30 sec. 1 min and 2 min; minimum period of 1 min at time points 5 min, 15 min, 30 min, 60 min). The dosage at which 50% of the animals are capable of remaining on the rod (i.e., ED50) was determined at each of these time points.
The results which have been obtained with the compound of the invention in the tests described previously are compiled in the following Table.
The in vivo agonistic activity of the compound of the invention at benzodiazepine receptors was demonstrated in the mouse operant conflict model of anxiety (for experimental details see: Martin et al., Acute and chronic administration of buspirone fails to yield anxiolytic-like effects in a mouse operant punishment paradigm. Pharmacol Biochem. Behav. 46: 905-910, 1993). In brief, adult female albino mice [Ibm:MORO(SPF); RCC Ltd., 4414 Fxc3xcllinsdorf, Switzerland] weighing approximately 30-40 g were used once they had been well trained over several months. The mice were individually housed in Macrolon(copyright) type I plastic cages with sawdust bedding. Tap water was available to the mice ad libitum, whereas access to the standard laboratory chow (Kliba Mxc3xchlen, Kaiseraugst, Switzerland) was restricted. Throughout the experiment the mice were maintained at approximately 80-85% of their free feeding body weight. Daily testing was done between 7 a.m. and 5 p.m. Such food-deprived mice were first trained to press a lever in a sound-attenuated operant box (circa 17xc3x9718xc3x9721 cm) in order to receive a 20-mg food pellet (Formula A/I; P. J. Noyes Company, Inc., Lancaster, N. H., USA) which was delivered into a food cup. Training sessions were 20 min and were generally given each weekday. Once a stable pattern of responding had been established, a new experimental phase was introduced: in 1 or 2 sessions per week (so-called xe2x80x9cconflict testsxe2x80x9d), an initial 5-min period during which each lever press was reinforced with a single food pellet was followed by an unsignaled 15-min period during which each lever press produced both a mild scrambled shock delivered through the stainless-steel grid floor and concomitant presentation of a single food pellet. In subsequent conflict tests, the mice received any of several reference benzodiazepine receptor full agonists (e.g., diazepam) or vehicle prior to testing. Only those mice who exhibited robust and stable drug-induced enhancement of punished responding were retained for use in subsequent experiments to investigate potential anxiolytics. Successive drug exposures were separated by a washout period of at least one week. Treatment was administered as an oral bolus circa 30 min prior to a conflict test. The evaluation lever-pressing within the punished portion of a conflict test session provides an accurate indication of the anxiolytic potential of a given compound. Data for each drug dose were compared separately with those of the vehicle condition (mean value for vehicle tests which were interspersed among the tests with drug) in the same animals using a one-tailed Wilcoxon matched-pairs, signed-rank test with a p-value equal or less than 0.05 accepted as statistically significant. The minimum effective dose (with statistically significant anxiolytic-like effect) for the compound of the invention was 3 mg/kg p.o. which indicates that it exhibits a potent anxiolytic-like effect typical of other benzodiazepine receptor agonists (e.g., diazepam).
Despite its exhibiting high affinity in vitro binding to benzodiazepine receptors, the compound of the invention nonetheless failed to reach an ED50 for rotarod impairment up to 10 mg/kg i.v. Having regard to its agonistic activity on the benzodiazepine receptors (e.g. active in the mouse operant conflict model), the compound of the invention can be used, for example, as an anxiolytic (tranquilizer), and/or an anticonvulsant, and/or for the non-sedative treatment of insomnia with the important advantage that these therapeutically relevant effects can be obtained across a wide dose range in the absence of appreciable sedation and/or motoric impairment.
The compound of the present invention was administered to mice in the above described rotarod test up to 100 mg/kg i.v. without fatalities occurring. In addition, rats (Ibm: RORO (SPF); RCC Ltd., 4414 Fxc3xcllinsdorf, Switzerland) received the compound of the present invention at 100 mg/kg i.v. without fatalities occurring.
The compound of the invention and pharmaceutically acceptable acid addition salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compound of the invention and pharmaceutically acceptable acid addition salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like can be used for aqueous injection solutions of water-soluble acid addition salts of the compound of the invention, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances.
It is an object of the present invention to provide medicaments containing the compound of the invention or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert excipient.
A further object of the present invention is a process for the production of such medicaments which comprises bringing the compound of formula I or pharmaceutically acceptable acid addition salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
The compound of the invention and pharmaceutically acceptable acid addition salts thereof can be used in accordance with the invention for therapeutic purposes, especially for anxiolytic and/or anticonvulsant and/or for the non-sedative treatment of insomnia. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 1 mg to 1000 mg should be appropriate. For intravenous or rectal administration a daily dosage of about 1 mg to 100 mg should be appropriate.
Finally, it is also an object of the present invention to provide the use of the above compound and of pharmaceutically usable acid addition salts thereof for the manufacture of medicaments, to be especially used as non-sedative and non-motor-impairing anxiolytic and/or anticonvulsant and/or non-sedative sleep-inducing medicaments.